1. Field of the Invention
Applicant's invention relates to a composition and method for treating certain ocular disorders and, particularly, macular edema and macular degeneration through the application of a topical carbonic anhydrase inhibitor and an ocular hypotensive agent or inotropic agents in an amount sufficient to improve visual function. Other macular disorders that can be treated are familial drusen, and macular disorders related to hypertension, angioma, papillitis, neuro retinitis (including Lebers stellate retinopathy) and other pigmentary retinal degenerative disorders.
2. Background Information
Macular edema is swelling within the retina in the critically important central visual zone at the posterior pole of the eye. An accumulation of fluid tends to distract the retinal neural elements from one another and from their local blood supply, creating a dormancy of visual function in the area. Usually, the process is self-limiting, but occasionally permanent visual disability results from macular edema Often times, the swelling may take many months to clear. The precise mechanism by which swelling is triggered is uncertain, but it is probable that certain natural metabolic toxins may play an important role in the disease process. Macular swelling may also follow the insertion of artificial lens implants and cataract surgery, particularly if there is a breach in the lens capsule which segregates the vitreous gel from the fluid-filled anterior chamber. Longstanding macular edema after cataract surgery is one of the most frustrating dilemmas in all of ophthalmology, and is remarkably common.
Macular edema is a common and alarming ocular problem, for which no useful form of therapy has been previously known.
Two types of cystoid macular edema are:
a. Those without vascular leakage: retinitis pigmentosa and other pigmentary retinal degenerative disorders, early stage macular hole, and choridal neovascularization; and PA1 b. Those with vascular leakage: diabetic retinopathy; branch retinal vein occlusion; intermediate uveitis; and ideopathicretinaltelangiectasis.
Another even more common chronic condition, which has typically been presumed to be irreversible, is macular degeneration. Instead of fluid accumulating in the outer retina, hard accumulations of lipofuscin, a metabolic waste product, tend to accumulate between the photoreceptors and the villi of the retinal pigment epithelium. These accumulations gradually enlarge, and in their early pathologic phase create discrete accumulations known as drusen. The lipofuscin is believed to accumulate as a result of the breaking off of the photoreceptor elements. Shedding of the cellular components of the photoreceptors is constantly occurring in a healthy retina. Good retinal pigment epithelial metabolism generally ensures a rapid clearance of such catabolic by-products of vision. The accumulation of this waste material retards the interaction between the retina and the retinal pigment epithelium from which nutrients arrive and through which catabolites are cleansed establishing a vicious cycle of catabolite accumulation. The accumulations not only block metabolic transfer between the retina and retinal pigment epithelium; they actually continue to undergo photoresponsive metabolism, constantly wasting precious NADH reducing power with no benefit.
An improved local circulation or a stabilization of membrane pH gradients might retard or prevent the accumulation of lipofuscin and break the vicious cycle of progressive blockage and waste of metabolic products passing to and from the retina.
As drusen accumulate in number and begin to coalesce, vast areas of retinal photoreceptors may become permanently disengaged from their neighboring retinal pigment epithelial villi. The sections of retina so affected become blind. Sadly, the greatest propensity among the aging population is for drusen to accumulate in the very central area of vision, the macula. Macular degeneration is the most common cause of legal blindness in the United States and Europe. Acetazolamide, a carbonic anhydrase inhibitor, has been given orally to treat macular edema but, while helpful, produces unpredictable responses and characteristically generates many systemic side effects. Even with the lower doses used in treatment of macular edema, the experience of physicians using acetazolamide (Diamox.RTM.) has been far from gratifying, with the large proportion of patients failing to continue therapy because of poor drug tolerance.
Currently, zinc in tablet form is administered to treat macular edema, but is also not effective and lacks any substantive clinical scientific support.
Whereas macular edema typically affects only one eye, macular degeneration typically involves both eyes and is usually fairly symmetric in its presentation and progression. There is virtually no family of European heritage in America without some relative who has suffered progressive loss of vision in their latter years as a result of macular degeneration. The problem is on the rise, and will continue to mount as the baby boom generation progresses towards maturity.
Macuar disease afflicts a small area of the very central retina, an area critical for reading and color vision. This is an area not typically affected to any practical extent by the disease glaucoma, which tends to diminish the surround vision (that is, the peripheral retina). This distinction is important, since the present invention is based upon the novel use of drugs currently used in the treatment of glaucoma.
It is important to understand that the retina is essentially a specialized part of the brain, and its circulation is very tightly regulated. Blood flow through the brain is typically constant in healthy individuals, whether running a marathon or sleeping. Obviously, huge variations in the inflow pressure of carotid artery blood to the brain occur throughout a typical day, and the vasculature in the cerebral cortex responds by adjusting its resistance. This is accomplished by constriction or dilation of the vessels throughout the brain. If the cerebrospinal fluid pressure is increased, creating, in effect, a stiffer vascular bed in the cerebral cortex, the blood vessels in the brain dilate to reduce intrinsic resistance, maintaining constant blood flow. This process is called autoregulation.
Autoregulation in the retina is analogous to that found in the brain, so if intraocular pressure is reduced, circulation in the retina is not necessarily increased. This point is clearly illustrated as a coincidental feature of two of the cases provided herein. Hyperventilation (to blow off carbon doxide and thereby reduce circulation to all the intrinsic vessels of the eye), or treatment with latanoprost (increasing the flow of clear fluid out of the eye) both produced significant eye pressure reduction, but visual function was actually simultaneously diminished. In each instance, however, if dorzolamide was coadministered there was visual enhancement.
Dorzolamide's profound effect on circulation is clearly not the result of any effect the drug might have on eye pressure, but arises as a result of its interference with autoregulation in the eye. The drug produces greater vascular compliance (that is to say, vessels remain effectively wide open even when other factors present would tend to produce vasoconstriction). In practice, drugs which reduce eye pressure tend to produce minimal changes in circulation and vision, and may in certain instances actually diminish both. It was discovered, quite unexpectedly, that a range of agents which reduce eye pressure, even those known to produce visual decrease while reducing pressure, can have a powerfully positive effect on both circulation and vision when dorzolamide is coadministered. The effects of this combination therapy appear to be profound.
In essence, once dorzolamide has uncoupled the autoregulatory system, which tends to balance changes in perfusion pressure with compensatory changes in intrinsic vascular tone, additional alterations in the perfusion pressure gradient (whether induced pharmacologically or by physiologic perturbation) are accompanied by a concomitant and corresponding change in retinal blood flow. There is no precedent for such a finding in the ophthalmological literature. The ability to uncouple autoregulation, manipulate perfusion pressure, and realize a corresponding physiologic effect opens up the potential for designing a range of specific treatments for a variety of retinal diseases.